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syn/anti Diastereoselectivity in the Aldol Reaction of Aldehydes with the C(3) Carbanion of 1,3‐Dihydro‐2 H ‐1,4‐benzodiazepin‐2‐one
Author(s) -
Marković Dean,
Hameršak Zdenko,
Višnjevac Aleksandar,
KojićProdić Biserka,
Šunjić Vitomir
Publication year - 2000
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/(sici)1522-2675(20000315)83:3<603::aid-hlca603>3.0.co;2-1
Subject(s) - chemistry , diastereomer , carbanion , stereochemistry , moiety , epimer , aldol reaction , trimethylsilyl , medicinal chemistry , catalysis , organic chemistry
The aldol reaction of the C(3) carbanion of 7‐chloro‐1,3‐dihydro‐1‐methyl‐5‐phenyl‐2 H ‐1,4‐benzodiazepin‐2‐one ( 2 ) with a series of aromatic and aliphatic aldehydes at −78° afforded threo / erythro diastereoisomers 3 – 16 of 7‐chloro‐1,3‐dihydro‐3‐(hydroxymethyl)‐1‐methyl‐5‐phenyl‐2 H ‐1,4‐benzodiazepinones, substituted at the C(3) side chain, in a ratio from 55 : 45 to 94 : 6 ( Scheme 1 ). Lewis acids exhibited limited effect on the syn / anti diastereoselectivity of this reaction, and kinetic control of the reaction was confirmed. 1 H‐NMR Data suggested the assignment of the threo relative configuration to the first‐eluted diastereoisomers 3 , 5 , 7 , and 9 on reversed‐phase HPLC, and the erythro configuration to the second‐eluted counterparts 4 , 6 , 8 , and 10 , respectively. The structures and relative configurations threo and erythro of the diastereoisomers 5 and 6 , respectively, were established by single‐crystal X‐ray analysis, confirming the assignment based on the 1 H‐NMR data. A tentative mechanistic explanation of the diastereoselectivity invokes the enolate anion of 1,3‐dihydro‐2 H ‐1,4‐benzodiazepin‐2‐one as the reactive species ( Scheme 2 ). Acid‐catalyzed hydrolytic ring opening of 3 afforded threo ‐ β ‐hydroxy‐phenylalanine 17 , whereas from 4 , the N ‐(benzyloxy)carbonyl derivative 18 of erythro‐ β ‐hydroxy‐phenylalanine was obtained ( Scheme 3 ); in both cases, neither elimination of H 2 O from the C(3)−CHOH moiety nor epimerization at C(3) were observed. This result opens a new pathway to various configurationally uniform α ‐amino‐ β ‐hydroxy carboxylic acids and their congeners of biological importance.